Saturated and unsaturated pregnane compounds and process of making same



' Patented June 29, 1943 SATURATED AND UNSATURATED PREG- NANE COMPOUNDSAND PROCESS OF MAKING SAME Karl Miescher, Riehen, and Albert Wettstein,

Basel, Switzerland, assignors to Ciba Pharmaceutical Products,Incorporated, Summit, N. J.

No Drawing. Application January 22, 1941, Se-

rial No. 375,540. 1 940 In Switzerland January 17,

11 Claims. (01. 260-397.5i

It has been found that saturated and unsaturated pregnane polycarbonylcompounds or their substitution products with, for example, additionaloxo or free or substituted hydroxyl groups, may be obtained by treatingpregnane- 20-ones, containing in the rings A or B merely double bondswith oxidizing agents, if desired after treatment with reducing andesterifying or etherifying agents, and finally, if desired, treatingwith hydrolyzing, acylating agents and/or oxidizing, dehydrogenating,water or acid eliminating agents.

The parent materials named are obtained, among other means, according tospecification Ser. No. 371,058, by the,degradation of the side chains ofcorresponding dimethyl-cyclopentanopolyhydrophenanthrene compoundscontaining side chains. They contain double bonds particularly in the 2,3, 4 or 5 positions.

By reducing agents, those agents are to be understood which are suitablefor the conversion of the -keto group into a carbinol group. Ifdesirable, the 20-carbinols thus obtained are converted into theiresters or ethers by the action of corresponding esterifying oretherifying agents in .a manner of itself known. In this instanceparticular use is made of esterifying agents which are capable ofintroducing aliphatic acid radicals, such as those of formic, acetic,propionic, nor iso-butyric, nor iso-valeric, caproic, capric, palmitic,or stearic acids, as well as those which introduce the radicals ofaromatic, fatty aromatic or inorganic acids, for example, the radicalsof benzoic, cinnamic or substituted carbonic acids. For theetherification, radicals are introduced of aliphatic oraliphatic-aromatic alcohols or phenols, for example, methyl, ethyl,benzyl, or triarylmethyl radicals and the like. A reduction of the20-keto group to the carbinol group and, if desired, subsequentesteriflcation or etherification is indicated if, in the subsequentoxidation, an oxidizing agent is used which will oxidize also the21-methy1 group standing in a-DOSitiOIl to the 20-keto group, shouldsuch a conversion be undesirable,

Oxidizing agents are now caused to react upon the unsaturated compounds,particularly those capable of introducingin a manner of itself knownoxygen or groups containing oxygen in the a-position to the double bondand, if desired.

to the keto group. These are, for example, chromic acid, seleniumdioxide, lead tetracylates, and so on, all of which lead to compoundscontaining oxo, hydroxy or substituted hydroxyl groups in theu-position. In place of those mentioned, it is also possible to causeagents to act on the unsaturated substances, particularly those havingdouble bonds in the 2- or 3-position, which are capable of adding oxygenor groups containing oxygen directly or indirectly to the double bonditself. For this purpose are suitable, for example, peroxides, such ashydrogen peroxide, if desired, in the presence of alkalies or metaloxides. Furthermore there are suitable per-acids, halogens, metaloxides, such as osmium tetroxide or vanadic acid, if desired, in thepresence of chlorates, also permanganates, lead tetracylates, aryliodosoacylates, or halogen-silver benzoate complexes. In order toconvert substituted hydroxyl groups or newly introduced epoxi groupingsinto free hydroxyl groups, the reaction products are further treated ifdesired with hydrolyzing agents, in which case it is also possible, bycarefully controlled action, only partially to hydrolyze thesubstituents in the rings A and B but not the substituted hydroxyl grouppossibly present in the l'l-position; on the other hand, partiallysubstituted polyhydroxy compounds may also be obtained by partialsubstitution of the free polyalcohols, making use of the particularlyready activity of, for instance, a hydyroxyl group in the 21-position inregard to acylation agents, for example.

In this manner, compounds of the dimethyl*cyclopentanopolyhydrophenanthrene series have been obtained whichcontain a keto group or a free hydroxyl group in the 20-position, ifdesired a free or acylated hydroxyl group in the 21- and/or 17-positionor an aldehyde group in the 21-position, and which contain in the ringsA or B keto groups or free or esterifled hydroxyl groups in m-POSitlOl'lto double bonds, or else-two adjacent free or esterified hydroxyl groupsin the rings A or B. From the compounds which contain hydroxyl groups inthe rings A or B or in the 20 position, the desired saturated orunsaturated pregnane polycarbonyl compounds or their substitutionproducts may subsequently be obtained in a manner of itself known 2assent? by the action of oxidizing or dehydrogenating agents or ofagents eliminating water or acid.

The following scheme illustrates by means oi formulae some or the abovereactions without in any way restricting the invention. For example, thecompound of Formula I or that 01 Formula VIII may be used as parentmaterial.

CH: CH;

III

means of a nickel catalyst, prepared, for example, by Rupes or Raneysmethod. After 1 molecule of hydrogen has been absorbed the hydrogenation is interrupted, the reaction solution is filtered from thecatalyst and the filtrate is evaporated in vacuo. The residue,consisting of a mixture of epimeric A -px'egnene-20-oles, is

on, I cm CH: CH: V

(\l--l co-cm1 Iv CH! CH (HI CH:

( -o O-GH) A v11 V\/ VI CHI CH: CH: CH:

,/\ll -4311, -l-C O-GH;

\/\) VIII Q/ 1x i cm on, on, on.

/ C0-C3, CO-CH:

I V X 0 XI at=free or substituted hydroxyl group.

Example 1 1 part of A -pregnene--one of the Formula I (prepared, forexample, according to specification Ser. No. 371,058 by partiallysplitting the side chain in A -cholestene) is dissolved in dissolved in'6 parts of absolute pyridine. 2 parts of propionic acid anhydride arenow added, and

the solution is maintained for 16 hours at room temperature when it ispoured into 50 parts of water. After the anhydride has decomposed, theresulting ester crystallizes, is removed by suction at the pump, washedwith water and dried parts of pure alcohol and is lwdrogenated by in thevacuum exsiccator. By recrystalization from hexane a mixture of epimericM-pregnene- 20-ole-propionates is obtained in the form of colorlesscrystals. These have the Formula In place of a catalytic hydrogenation,the reduction may be carried out by means of nascent hydrogen, forexample, of an alkali metal and an alcohol, by means of an organo-metalcompound prone to form unsaturated hydrocarbons, such asiso-propyl-magnesium iodide, or even by biochemical or electrochemicalmeans. In place of propionic acid anhydride, other propionylating agentsmay naturally be used, for example, a propionic acid halide, or otherdesired esters or ethers may be prepared.

In place of the radical oi propionic acid, other ester or ether radicalsmay be introduced, for example those named before, or the new carbinolgroup may rest unprotected.

If, instead of using A -pregnene-20-one as parent substance, 8. parentmaterial which is unsaturated in another position be used. for example,A A*- or A-pregnene-20-one, the corresponding unsaturated product isanalogously obtained.

Thus quite generally as intermediates pregnane derivatives are obtainedcontaining in the rings A and B merely a double bond and in 20-positiona free, esterified or etherified hydroxyl group; for example the A 11 A-or M-pregnene-20- ole-acylates.

1 part of the mixture of epimeric M-pregnenealready described is heatedwith 2.2 parts of lead tetracetate and 25 parts of glacial acetic acidfor some time at 75 C. with exclusion of moisture. The reaction mixtureis then filtered, the filtrate is evaporated in vacuo, water is addedand the resulting mixture is exhaustively extracted with ether. Theethereal solution is washed with soda solution and water, dried andevaporated. The residue is taken up in hexane and is chromatographedwith the aid of aluminium oxide. A pregnene 3,20 diol 3 acetate 20propionate is obtained as chief product (Formula The diester may besaponified by boiling for 2 hours with a 5 percent solution of potassiumhydroxide in methanol. In this way, a preparation of sterically isomericA -pregnene-3,20- diols (Formula VI; :r=OH) is obtained. Asft-unsaturated alcohols, these compounds give a strongly positivereaction with trichloroacetic acid. In order to oxidize or dehydrogenatethem, they are treated, either with intermediate protection oi thedouble bond by bromination, with chromic acid in glacial acetic acid,or, without this intermediate protection, with an aluminium alcoholatein the presence of a ketone, such as acetone or cyclohexanone. In thisway, the known a -pr s ene-azo-dione (Progesterone) oi Formula VIII isobtained.

For the first omdation, selenium oxide or chromic acid, for example, maybe used instead of lead tetracetate. In this case, A-pregnene-3,20-diol-20-propionates or -3-one-20-olepropionates areprimarily obtained, which are subsequently saponified and then may alsobe converted into progesterone by the action of oxidizing ordehydrogenating agents in a manner of itself known.

Example 2 1 part or A -pregnene--one (Formula I) is dissolved in 50parts of glacial acetic acid; a solution of 1.2 parts of chromiumtrioxide in a little water is added and the whole is stirred for 12hours at room temperature, after which400 P rts of water are added. Thereaction mixture is exhaustively extracted with ether, and the etherealsolution is washed with bicarbonate solution and water, dried andevaporated in vacuo. From the residue, progesterone (A-pregnene-3,20-dione) of Formula VII, in addition to corresponding6-oxoand 3,6-dioxo-compounds, is obtained by fractional crystallization,adsorption or sublimation.

In place of chromic acid, selenium dioxide or a lead tetracylate, forexample, may also be used for the oxidation. In this case, M-3-hydroxyor-acyioxy compounds with an aidehyde group in the 21-Position (FormulaII) or an acyloxy group in the 21- and/or 17-position (such as that ofFormula III) are primarily obtained. The latter compound may beconverted into desoxy-corticosterone-acylates or others, for exampleinto desoiw-corticosterone-acetate (21-acetoxy-pregnene-3,20-dione) ofFormula IV (-|=-OCQ-CH3) by saponification of the ester groups,subsequent partial acylation or etherification in the 21-position andaction of oxidizing or dehydrogenating agents in a manner of itselfknown.

Example 3 1 part of A -pregnene-20-one of Formula VIII (prepared, forexample, according to specification Ser. No. 371,058 by partiallysplitting the side chain in A -cholestene) is dissolved in ether and anethereal solution of 1.1 equivalents oi osmium tetroxide is added. Thereaction mixture is allowed to stand .for 5 days at room temperature,after which it is completely evaporated at a bath temperature of 30 C.,and the residue is heated in aqueous-alcoholic solution for 2 hours with2 parts of sodium sulphite. For the reductive hydrolysis of the osmicacid ester other reducing agents, for example, acid agents, such asascorbic acid or formic acid, may be used. The filtered reductionmixture is poured into water, exhaustively extracted with chloroform,the chloroform solution is washed with water, dried and evaporated. Fromthe residue, pregnene-3,4-diol-20-on (Formula X; a:=OH) is obtained byrecrystallization from acetone or dilute methanol.

In place of the direct addition of the two hydroxyl groups to the doublebond, an oxide ring, or either one or both of the hydroxyl groupsinsubstituted form, for example, in acylated form, may first be added,in which case use is made of reagents of themselves known, for example,of the reagents mentioned above in this specification. The oxide ring orsubstituted hydroxyl groups may subsequently be saponified, if desired,the latter wholly or partially.

As the final stage of the process, for example, agents or means whicheliminate water such as alkali bisulphates, dry vacuum distillation ormany others, may be caused to act on the pregnane-3,4-diol-20-one in amanner or itself known. If the hydroxyl group in the 4- and/or3-position be present in esterified form, which is the case, forexample, when peracetic acid, lead tetrabenzoate or a halogen-silverbenzoate complex has been used for the hydroxylation, then an agentwhich eliminates acid is used in place of the above agents, for example,zinc dust in toluene or xylene, alkali carbonates, if

desired, after the action of oxidizing or dehydrogenating agents if onehydroxyl group is free, in order to convert this into a keto. group.'-In this manner, for example, pregnane-3,20-dione of Formula XI orprogesterone of Formula VII may be obtained.

What we claim is:

1. A pregnane derivative containing in the rings A and B merely a doublebond, namely in one of the positions 2, 3, 4 and 5, and in 20-p0'sitiona member of the group consisting of a hydroiwl group and a group whichupon hydrolysis is convertible into a hydroxyl group.

2. Process for the manufacture of saturated and unsaturated pregnanepolycarbonyl compounds and their substitution products, comprisingtreating a pregnane derivative containing in 20-position a member of thegroup consisting of a keto group and a free, esterified and etherifiedhydroxyl group, and containing in the rings A and B merely double bonds,with an oxidizing agent capable of introducing groups containing oxygeninto the said rings.

3. Process for the manufacture of saturated ing treating a pregnanederivative containing in 20-position a member of the group consisting ofa keto group and a free, 'esterified and etherifled hydroxyl group, andcontaining in the rings A and B merely a double bond, with an oxidizingagent capable of introducing esterified hydroxyl groups into the saidrings, and then with a hydrolyzing agent and finally with a member ofthe group consisting of an oxidizing and a dehydrogenating agent.

5. Process for the manufacture of saturated and unsaturated pregnanepolycarbonyl compounds and their substitution products, comprisingtreating a pregnane derivative containing in ZO-pcxsition a member ofthe group consisting of a keto group and a free, esterified andetherified hydroxyl group, and containing in the rings A and B merely adouble bond, with an oxidizing agent capable of introducing esterifiedhydroxyl groups into the said rings, and then with a hydrolyzing agentand finally with a water eliminating agent.

6. Process for the manufacture of saturated and unsaturated pregnanepolycarbonyl compounds and their substitution products, comprisingtreating a pregnane derivative containing in 20-position an esterifiedhydroxyl group, and containing in the rings A and B merely a doublebond, with an oxidizing agent capable of introducing esterified hydroxylgroups into the said rings, then saponifying all esterified hydroxylgroups present with, a, .hydrolyzing agent, par? tially esterifying withan acylating agentand finally treating with a member of the groupconsisting of an oxidizing agent and a dehydrogenating agent capable ofconverting free hydroxyl to keto groups.

7. Process for the manufacture of saturated and unsaturated pregnanepolycarbonyl compounds and their substitution products. comprisingtreating a pregnane derivative containing in 20-position a member of"the group consisting of a krdo group and a free, esterified andetherified hydroxyl group, and contaimng in the rings A and B merely adouble bond, with an oxidizing agent capable of introducing freehydroiwl groups into the said rings, and finally with a member of thegroup consisting of an oxidizing and a dehydrogenating agent, capable oftransforming hydroxyl into-keto groups.

8. Process for themanufacture"of saturated and unsaturated pregnane"polycarbonyl compounds and their substitution products, comprisingtreating a pregnane'derivative containing in 20-position a member'of thegroup consisting of a keto group and a freegesterifled and etherifiedhydroxyl group, and'containing in the rings A and B merely a doublebond, with an oxidizing agent capable of introducing free and esterifledhydroxyl groups into the said rings, then with a member of the groupconsisting of an oxidizing and a dehydrogenating agent, capable oftransforming free hydroxyl into keto groups, and finally eliminating theintroduced esterified hydrorwl groups with an acid eliminating agent.

9. A A -pregnene-2o-ole of the formula on; on:

CHOHCH1 (Ha CH1 OCOCzH:

-tHcH. 7 03 11. A pregnane derivative of the formula (Ha CH:

T-onzcrn

